Infiltration of immunocompetent cells, particularly neutrophils, from blood into tissues, which characterizes the basic morbidity of inflammation, is deeply implicated to the formation of edema caused by the subsequent leakage of blood components and to the progress of the inflammatory symptoms accompanying with the tissue destruction. The diseases in which the abnormality of immunity is considered to be involved in the progress of the inflammatory symptoms include, for example, non-specific inflammatory diseases such as chronic arthritis; diseases of respiratory organs such as chronic obstructive pulmonary disease and pulmonary bronchitis based on chronic respiratory tract infection, adult respiratory distress syndrome, and bronchi-obstructive type asthma classified as the adult type asthma; colon disease which is one of intestinal diseases; and psoriasis which is one of dermatitis.
In addition to various inflammatory cytokine and chemical mediators produced by neutrophils, proteases are considered to play a significant role in the induction of edema and inflammatory symptoms accompanying with tissue destruction, which follow the neutrophile infiltration. Protease is an enzyme serving to degrade elastin and collagen as fiber proteins constituting interstitial connective tissue in organs such as lung, cartilage, blood vessel wall and skin of higher animals. Moreover, protease possesses cytotoxic activity to cells of higher animals. In particular, elastase, i.e., a protease which degrades elastin, is considered to play a great important role. Such being the situation, an elastase inhibitor has come to be hopefull to become an effective prophylatic and therapeutic agent for the above-noted diseases, as well as for various diseases including pancreatitis, nephritis, arteriosclerosis and septicemia, due to the destruction and deterioration of tissue caused by elastase and the cytotoxity of the elastase.
Some peptide or non-peptide compounds have already been reported as serine protease inhibitors such as elastase inhibitor. For example, non-peptide inhibitors are reported in "Journal of the Biochemistry, Vol. 257, pages 5085 to 5091 (1982)", "Journal of the Medicinal Chemistry, Vol. 30, pages 1017 to 1023 (1987)", "Journal of the Medicinal Chemistry, Vol. 31, pages 1052 to 1061 (1988)", "Journal of the Medicinal Chemistry, vol. 33, pages 464 to 479 (1990)", Published Unexamined Japanese Patent Application No. 1-308227, WO 88/9790, and EPO 337549.
On the other hand, a large amount of endogenous protease inhibitors are present together with protease in the inflammatory regions. This may suggest that it is insufficient to utilize the protease inhibitory activity alone for preventing or suppressing the initiation and progression of the inflammation. For example, the hypothesis on the induction of chronic arthritis has been proposed by Lower et al in "Journal of Rheumatol, Vol. 14, page 49 (1987)". It's indicated that activated neutrophils once infiltrating into cartilage, organs and so on, are considered not to be interfered their functions by a protease inhibitor and are considered to cause the destruction of cartilage, organ and so on.
With above informations and a hypothesis together, it is of high demand to develop a medicine which acts as an effective anti-inflammatory agent suppressing the neutrophil function, thereby preventing the infiltration of neutrophils migrating into the inflammatory region and also inhibiting the tissue destruction by the action of elastase excreted from the infiltrated neutrophils.